Immunohistochemical (IHC) Testing Drives Tailored Therapies for HER2-Positive Cancers

Immunohistochemical (IHC) Testing Drives Tailored Therapies for HER2-Positive Cancers

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April 25, 2024

Clinical Relevance: IHC testing is now crucial for oncologists as it identifies specific tumor antigens to help guide personalized treatment strategies.


Immunohistochemical (IHC) testing is quickly becoming an essential function in clinical oncology practice, particularly with the rise of antibody-drug conjugates (ADCs).

IHC testing is critical for identifying unique antigens expressed on tumor cells, which in turn determines whether a patient is a suitable candidate for ADC therapy. Armed with this information, oncologists are able to tailor ADC treatments to the unique molecular profile of each patient’s cancer.  

The tumor-agnostic capability of ADCs allows them to effectively target and treat multiple cancer types based solely on the presence of the specific antigens, leading to better outcomes. 

“We can analyze what the tumor is doing now in terms of acquiring new mutations and the landscape of its targets or traditional targets that may be useful,” says Dr. Anupama Nehra, the clinical director of hematology/oncology at the Rutgers Cancer Institute at University Hospital in New Jersey.”Results often come back within 48 hours so treatment decisions can be made quickly.”

Related: How ADCs are Used in Advanced Bladder Cancer

Understanding the Structure and Function of ADCs: The Case of Enhertu

IHC testing, already a routine and cost-effective method in oncological pathology, plays a crucial role in the use of Enhertu, an ADC targeting HER2 (Human Epidermal Growth Factor Receptor 2) recently approved by the US Food and Drug Administration (FDA).

ADCs cleverly combine precision targeting with powerful cancer-killing agents. Enhertu exemplifies this approach, consisting of three main components: a HER2-targeting antibody, a cleavable linker, and a cytotoxic payload. 

The monoclonal antibody targets and binds to HER2 receptors on cancer cells, sparing healthy tissues. Once bound, the complex is internalized by the cancer cell, where the linker is enzymatically cleaved, releasing a potent topoisomerase I inhibitor that interferes with DNA replication, leading to tumor cell death.

“It’s a bioengineered drug that essentially has more of an effect on the tumor cells compared to normal cells. So use of this medication actually helps minimize some of the effects on the normal tissue, but maximize the effects on the tumor tissues,” Dr. Nehra says.

Nehra adds that the drug delivers even more benefit thanks to a phenomenon called “the bystander effect”.

“This basically means that the surrounding tumor cells are also targeted by the medication,” she explains. 

By assessing the level of HER2 expression, scored from 0 to 3+, IHC can identify patients with high HER2 levels. 

  • 0: No HER2 protein overexpression is detected. The cancer is considered HER2-negative.
  • 1+ (Score of 1): A small amount of HER2 protein is present, but it’s still considered HER2-negative.
  • 2+ (Score of 2): There’s an intermediate level of HER2 protein. This score is borderline, and further testing, usually with FISH, is recommended to clarify HER2 status.
  • 3+ (Score of 3): There’s a high level of HER2 protein overexpression, and the cancer is considered HER2-positive. This indicates that the cancer may respond to HER2-targeted therapies.

Related: Treatment of Her2-Positive Breast Cancer

Clinical Validation of Enhertu’s Efficacy

Enhertu was Initially used as a breast cancer therapy. In the DESTINY-Breast01 trial, for example, Enhertu showed a 61.4% objective response rate in HER2-positive metastatic breast cancer patients who had previously received other HER2-targeted therapies. The responses were durable, with a median length of 20.8 months. 

More recently, the FDA has granted accelerated approval for Enhertu to treat adults with unresectable or metastatic HER2-positive solid tumors under a tumor-agnostic indication, provided these tumors have no satisfactory alternative treatments. 

“The drug was actually previously approved for breast cancer and gastric cancer and cancer in the lower end of the esophagus,” Dr. Nehra states. “Now it is approved for lung cancer, gynecological cancers, biliary tract cancers – any type of cancer which expresses a target in the cancer cells called HER2-positive.”

Enhertu’s benefits for high-expressing HER2 tumors are highlighted by its performance in numerous clinical trials

  • Biliary tract cancer: Median progression-free survival (PFS) was 6.9 months; median overall survival (OS) was 13.4 months; confirmed objective response rate (ORR) was 37.1%; median duration of response (DoR) was 11.3 months.
  • Pancreatic cancer: PFS was 6.9 months; OS was 13.4 months; ORR was 4%.
  • Bladder cancer: PFS was 6.9 months; OS was 13.4 months; ORR was 51.4%; DoR was 19.4 months.
  • Cervical and endometrial cancer: PFS was 6.9 months; OS was 13.4 months; ORR was 37.1%; DoR was 11.3 months.
  • Lung Cancer: Median PFS was 4.89 months; OS was 12.78 months; ORR was 27%.
  • Breast Cancer: Median PFS was 11.9 months; OS was 21.1 months; DoR was 22.1 months.
  • Gastric Cancer and Gastroesophageal Junction Cancer: Median PFS was 6.9 months; OS was 13.4 months; ORR was 37.1%; DoR was 11.3 months.
  • Colorectal Cancer (HER2 Overexpressed): Median PFS was 6.9 months; OS was 13.4 months; ORR was 4%.

Dr. Deanna Gerber, a gynecologic oncologist at the Perlmutter Cancer Center at NYU Langone Hospital in Long Island, NY says that the benefits have been especially exciting to see for gynecological cancers such as ovarian and cervical cancer.

“In our recurrent gynecologic cancer patients such as cervical cancer, endometrial cancer and ovarian cancer patients who have received prior therapy, we usually see pretty low response rates. But this drug showed very impressive response rates –greater than 40% for most gynecologic cancers with 2+ IHC scores or higher,” she says.

While it’s not a cure-all, Dr. Gerber says that Enhertu adds a critical tool in the fight against these aggressive tumors. For patients facing limited treatment possibilities, that means real hope.

What the Future Holds

Enhertu is being investigated for its potential use in other HER2-positive cancers, including salivary gland and endometrial cancers, as well as other solid tumors with HER2 mutations or overexpression. These studies aim to broaden the therapeutic impact of Enhertu by exploring its efficacy against a diverse range of cancers not typically associated with HER2 targeting.

This approval also underscores the importance of testing for HER2 across a broad range of tumors to identify patients who could benefit from this targeted therapy, especially those with advanced cancer who have limited treatment options.  

If a patient’s tumor tests high for HER2, oncologists may consider using Enhertu even if it hasn’t been specifically tested for that tumor type.

This makes IHC testing a crucial step in the management and treatment planning for patients with various solid tumors.

However, Dr. Gerber says ADCs like Enhertu aren’t a cure all and they are not right for every patient. 

“If they don’t express HER2, then I would not treat them with this medication at this time with the data that we have,” she clarifies.

But, she adds, she might order further testing to better understand the nature of the tumor.

Related: Study Raises Clinical Considerations for Strategic Immunotherapy Use in Metastatic Cancer Care